Significance- Lung cancer is the leading cause of cancer deaths with over 200,000 new diagnoses annually. Survival rate of lung cancer patients is correlated with the extent of lymph node metastasis. Standard care includes chemotherapy, radiation, and/or surgery. Cisplatin is a first-line chemotherapy for lung cancer, but systemic intravenous (IV) delivery is confounded by various toxicities (renal toxicity is dose limiting), poor penetration into tumors and lymph nodes, organ damage, and resistance. Solution: Delivery of high-dose, targeted cisplatin directly to lung cancers can increase the therapeutic window, increasing efficacy and renal safety, even in platinum-resistant patients. Product- The product of this SBIR will be pulmonary delivery of an aerosolized chemotherapeutic, HylaPlat, that delivers high-dose targeted cisplatin directly to the lungs targeting primary lung cancers and lymphatic metastases to replace IV cisplatin therapy for locally advanced CD44+ non-small cell lung cancers. Innovation # 1 Formulation: HylaPlat's formulation is a hyaluronan (HA)- cisplatin conjugate. Innovation # 2 Aerosol Delivery Directly to Lungs: Direct administration to the lungs deposits HylaPlat at the site of action. The innovation of HylaPlat, which is the combination of its formulation and aerosolized delivery, has four major advantages: (1) HA targets CD44+ tumor cells. CD44 expression is associated with metastasis and poor prognosis. (2) High drug levels in lungs. (3) High drug levels in lymph nodes targets metastases. (4) Improved PK. Collectively, these advantages are expected to result in significantly increased efficacy and renal safety over standard-of-care IV cisplatin. Unlike many targeted cancer therapies in development that are limited to specific types of cancers, HylaPlat, has demonstrated efficacy in models of several cancer types. Most strikingly, 4 or fewer doses of peri-tumoral HylaPlat achieved a complete response in 3 of 7 dogs (43%) presenting at a veterinary hospital with naturally-occurring age-related head and neck squamous cell carcinomas, significantly better than a 9% success rate with IV cisplatin. Therefore, the major unanswered question is whether pulmonary delivery of aerosolized HylaPlat is safe and effective for targeting lung cancers. Hypothesis- Pulmonary delivery of aerosolized HylaPlat will be more efficacious and more tolerable than IV cisplatin in rodent models of lung cancer. Preliminary results indicate that a single dose of aerosolized HylaPlat significantly attenuates the growth of lung cancer allografts in immunocompetent mice. In this project, we will establish feasibility of pulmonary delivery of aerosolized HylaPlat for lung cancer by demonstrating increased efficacy and preferential target-tissue distribution and pharmacokinetics over standard-of-care IV cisplatin in rodent models. This Phase I SBIR will position aerosolized HylaPlat for IND- enabling studies (SBIR Phase II award), after which Hylapharm will seek partnerships for human phase I clinical trials.